Cemented Total Knee Replacement (TKR) is an established and reliable procedure that seeks to restore joint mobility and relieve pain associated with rheumatoid or osteo-arthritis. While over 600,000 knees are implanted with great success annually, a substantial portion (~15%) fail prematurely. Most long-term failures are due to a process known as aseptic loosening, where the mechanical interlock between trabecular bone and cement weakens due to the erosion (osteolysis) of bone. This allows the implant to migrate and become painful, necessitating a revision surgery. Aseptic loosening is most often attributed to osteolysis caused by the body's response to articulating surface polyethylene (PE) wear accumulation at the implant-bone interface. Importantly, short-term failures can and do occur, and these may not be related to PE debris since the amount of debris created is proportional to time in service. Recent studies of postmortem retrieved, clinically- successful, human TKRs point to an additional, contributing factor in aseptic loosening: in the short-term, there is >50% resorption of the trabeculae that initially interlock with the bone cement, but this occurs without much wear to the PE articulating surface. This suggests early loss of fixation is caused by an alternate mechanism. In the postmortem studies, it was observed that when joint loads are applied to the TKRs, synovial fluid and/or marrow is pumped through small gaps between the interlocked trabeculae and cement. The fluid shear stresses (FSS) generated from the fluid pumping is estimated to be supraphysiologic, and will likely have an effect on the osteoblasts and osteoclasts that line the surface of trabecular bone. The overall goal of this study is to show that these supraphysiologic fluid shear stresses are sufficient to cause resorption of the trabeculae that interlock with cement, and that this can occur without PE debris. The Specific Aims of this project are to show: 1) trabecular resorption at the interface occurs in the absence of PE debris, 2) supraphysiologic FSS can affect resorption by increasing osteoclast activity (mineral resorption) while decreasing osteoblast activity (mineral deposition), and 3) PE debris accumulation and supraphysiologic FSS act in concert to produce more resorption than either process alone. We will first identify the location and amount of PE debris at the cement-bone in postmortem retrieved, clinically successful, human tibial components of TKA with short term (<5 years) and long term (>10 years) use. We expect short-term devices to contain little to no wear at the interface, but have extensive bone resorption. In contrast, we expect long-term devices to have both substantial PE wear and resorption. Next, we will elucidate the effects of FSS ranging from sub to supraphysiologic levels on in vitro cell lines of osteoclasts and osteoblasts, with or without PE debris. These experiments will allow us to first, quantify PE debris in direct, physical relation to the cement-trabeculae interface of retrievals, and second, differentiate the effects of high FSS from PE debris. Overall, the goal of this work is to extend the long-term success of TKRs.